Influence of chronic intermittent hypoxia on growth associated protein 43 expression in the hippocampus of young rats

This study aimed to explore the pathological change to hippocampal neurons and the expression of growth associated protein 43 in 21-day-old young rats following chronic intermittent hypoxia. Hematoxylin-eosin staining results showed varying degrees of degeneration and necrosis in hippocampal neurons depending on the modeling time. Immunohistochemistry revealed that growth associated protein 43 expression in young rats following chronic intermittent hypoxia decreased, but that levels were still higher than those of normal rats at each time point, especially 4 weeks after modeling. During 1 5 weeks after modeling, a slow growth in rat weight was observed. Experimental findings indicate that chronic intermittent hypoxia may induce growth dysfunction and necrosis of hippocampal neurons, as well as increase the expression of growth associated protein 43 in young rats.

Atorvastatin Attenuates Myocardial Hypertrophy Induced by Chronic Intermittent Hypoxia In Vitro Partly through miR-31/PKCε Pathway

Atorvastatin is proven to ameliorate cardiac hypertrophy induced by chronic intermittent hypoxia （CIH）. However, little is known about the mechanism by which atorvastatin modulates CIH-induced cardiac hypertrophy, and whether specific hypertrophyrelated microRNAs are involved in the modulation. MiR-31 plays key roles in the development of cardiac hypertrophy induced by ischemia/hypoxia. This study examined whether miR-31 was involved in the protective role of atorvastatin against CIH-induced myocardial hypertrophy. H9c2 cells were subjected to 8-h intermittent hypoxia per day in the presence or absence of atorvastatin for 5 days. The size of cardiomyocytes, and the expression of caspase 3 and miR-31 were determined by Western blotting and RT-PCR, respectively. MiR-31 mimic or Ro 31-8220, a specific inhibitor of protein kinase C epsilon （PKCε）, was used to determine the role of miR-31 in the anti-hypertrophic effect of atorvastatin on cardiomyocytes. PKCε in the cardiomyocytes with miR-31 upregulation or downregulation was detected using RT-PCR and Western blotting. The results showed that CIH induced obvious enlargement of cardiomyocytes, which was paralleled with increased atrial natriuretic peptide （ANP）, brain natriuretic peptide （BNP）, and slow/beta cardiac myosin heavy-chain （MYHT） mRNA levels. All these changes were reversed by the treatment with atorvastatin. Meanwhile, miR-31 was increased by CIH in vitro. Of note, the atorvastatin pretreatment significantly increased the mRNA and protein expression of PKCε and decreased that of miR-31. Moreover, overexpression of miR-31 abolished the anti-hypertrophic effect of atorvastatin on cardiomyocytes. Upregulation and downregulation of miR-31 respectively decreased and increased the mRNA and protein expression of PKCε. These results suggest that atorvastatin provides the cardioprotective effects against CIH probably via up-regulating PKCε and down-regulating miR-31.

Adiponectin Ameliorated Pancreatic Islet Injury Induced by Chronic Intermittent Hypoxia through Inhibiting the Imbalance in Mitochondrial Fusion and Division

Objective This study aimed to assess the protective value of adiponectin(APN)in pancreatic islet injury induced by chronic intermittent hypoxia(CIH).Methods Sixty rats were randomly divided into three groups:normal control(NC)group,CIH group,and CIH with APN supplement(CIH+APN)group.After 5 weeks of CIH exposure,we conducted oral glucose tolerance tests(OGTT)and insulin released test(IRT),examined and compared the adenosine triphosphate(ATP)levels,mitochondrial membrane potential(MMP)levels,reactive oxygen species(ROS)levels,enzymes gene expression levels of Ant1,Cs,Hmox1,and Cox4 i1 which represented mitochondrial tricarboxylic acid cycle function,the protein and gene expression levels of DRP1,FIS1,MFN1,and OPA1 which represented mitochondrial fusion and division,and the protein expression levels of BAX,BCL-2,cleaved Caspase-3,and cleaved PARP which represented mitochondrial associated apoptosis pathway of pancreatic islet.Results OGTT and IRT showed blood glucose and insulin levels had no differences among the NC,CIH and CIH+APN groups(both P>0.05)at 0 min,20 min,30 min,60 min,120 min.However,we found that compared to NC group,CIH increased the ROS level,reduced ATP level and MMP level.The islets of CIH exposed rats showed reduced gene expression levels of Ant1,Cs,Hmox1,and Cox4 i1,decreased protein and gene expression levels of MFN1 and OPA1,increased protein and gene expression levels of DRP1 and FIS1,increased protein expression levels of cleaved Caspase-3 and cleaved PARP,with lower ratio of BCL-2/BAX at protein expression level.All the differences among three groups were statistically significant.APN treated CIH rats showed mitigated changes in the above measurements associated with islet injuries.Conclusion APN may ameliorate the pancreatic islet injury induced by CIH via inhibiting the imbalance in mitochondrial fusion and division.

Chronic intermittent hypoxia induces cardiac inflammation and dysfunction in a rat obstructive sleep apnea model

Chronic intermittent hypoxia is considered to play an important role in cardiovascular pathogenesis during the development of obstructive sleep apnea（OSA）.We used a well-described OSA rat model induced with simultaneous intermittent hypoxia.Male Sprague Dawley rats were individually placed into plexiglass chambers with air pressure and components were electronically controlled.The rats were exposed to intermittent hypoxia 8 hours daily for 5weeks.The changes of cardiac structure and function were examined by ultrasound.The cardiac pathology,apoptosis,and fibrosis were analyzed by H＆E staining,TUNNEL assay,and picosirius staining,respectively.The expression of inflammation and fibrosis marker genes was analyzed by quantitative real-time PCR and Western blot.Chronic intermittent hypoxia/low pressure resulted in significant increase of left ventricular internal diameters（LVIDs）,endsystolic volume（ESV）,end-diastolic volume（EDV）,and blood lactate level and marked reduction in ejection fraction and fractional shortening.Chronic intermittent hypoxia increased TUNNEL-positive myocytes,disrupted normal arrangement of cardiac fibers,and increased Sirius stained collagen fibers.The expression levels of hypoxia induced factor（HIF）-l α,NF-κB,IL-6,and matrix metallopeptidase 2（MMP-2） were significantly increased in the heart of rats exposed to chronic intermittent hypoxia.In conclusion,the left ventricular function was adversely affected by chronic intermittent hypoxia,which is associated with increased expression of HIF-lα and NF-κB signaling molecules and development of cardiac inflammation,apoptosis and fibrosis.

Effect of NADPH Oxidase Inhibitor Apocynin on the Expression of Hypoxia-induced Factor-1α and Endothelin-1 in Rat Carotid Body Exposed to Chronic Intermittent Hypoxia

The effects of nicotinamide adenine dinucleotide phosphate （NADPH） oxidase inhibitor apocynin on the enhanced hypoxia induced factor-let （HIF-lct） and endothelin-1 （ET-1） expression, elevated systolic blood pressure under chronic intermittent hypoxia （CIH） condition and its action mechanism were investigated. Thirty healthy 8-week old Sprague-Dawley （SD） male rats were randomly divided into three groups （n=10 each）： sham group, CIH group, and apocynin-treated CIH group. Tail artery systolic blood pressure was measured by tail-cuff method. Real-time fluorescence quantitative polymerase chain reaction （PCR） was used to detect the mRNA expression of HIF-lu and ET-1 in the carotid body, and the HIF-1a protein expression was examined by using Western blotting. The levels of malondialdehyde （MDA） and superoxide dismutase （SOD） were determined by using colorimetric method. In addition, the plasma ET-1 and HIF-1a levels were measured by using enzyme-linked immunosorbent assay. It was found that CIH exposure was associated with increased MDA levels, and apo- cynin-treated CIH animals showed reduction in MDA levels. Apocynin treatment prevented CIH-induced hypertension as well as CIH-induced decrease in SOD. The increases of HIF-1a and ET-1 mRNA along with HIF-la protein expression in the carotid body, and elevated circulating HIF-1a and ET-1 levels were observed in CIH-exposed animals. Treatment with apocynin significantly decreased the ET-1 mRNA, HIF-lct protein expression and circulating HIF-la level in CIH-exposed animals, and there was no statistically significant difference in the HIF-lu mRNA expression between CIH group and apo- cynin-treated group. These results indicated that apocynin alleviated CIH-induced hypertension by inhibiting NADPH oxidase, further leading to the reduced vasoconstrictor ET-1 level and oxidative stress. HIF-1a/ET-1 system signal pathway may interact with CIH-induced NADPH oxidase-dependent oxidative stress. Inhibition of NADPH oxidase activity may hopefully serve as a useful strategy for prevention and treatment of obstructive sleep apnea hypopnea syndrome-induced hypertension.

Impairment of cognitive function and reduced hippocampal cholinergic activity in a rat model of chronic intermittent hypoxia

The present study established a rat model of chronic intermittent hypoxia （CIH） to simulate obstructive sleep apnea syndrome. CIH rats were evaluated for cognitive function using the Morris water maze, and neuronal pathology in the hippocampus was observed using hematoxylin-eosin staining. In addition, hippocampal choline acetyl transferase （CHAT） and nicotinic acetylcholine receptor （nAChR） expression was determined by immunohistochemistry. Our results revealed necrotic hippocampal neurons, decreased ChAT and nAChR expression, as well as cognitive impairment in CIH rats. These results suggest that hippocampal neuronal necrosis and decreased cholinerqic activity may be involved in CIH-induced cognitive impairment in rats.

Shengmaisan combined with Liuwei Dihuang Decoction alleviates chronic intermittent hypoxia-induced cognitive impairment by activating the EPO/EPOR/JAK2 signaling pathway

Chronic intermittent hypoxia(CIH),a principal pathophysiological aspect of obstructive sleep apnea(OSA),is associated with cognitive deficits.Clinical evidence suggests that a combination of Shengmaisan and Liuwei Dihuang Decoctions(SMS-LD)can enhance cognitive function by nourishing yin and strengthening the kidneys.This study aimed to assess the efficacy and underlying mechanisms of SMS-LD in addressing cognitive impairments induced by CIH.We exposed C57BL/6N mice to CIH for five weeks(20%-5%O_(2),5 min/cycle,8 h/day)and administered SMS-LD intragastrically(15.0 or 30 g·kg^(-1)·day)30 min before each CIH session.Additionally,AG490,a JJanus kinase 2(JAK2)inhibitor,was administered via intracerebroventricular injection.Cognitive function was evaluated using the Morris water maze,while synaptic and mitochondrial structures were examined by transmission electron microscopy.Oxidative stress levels were determined using DHE staining,and the activation of the erythropoietin(ER)/ER receptor(EPOR)/JAK2 signaling pathway was analyzed through immunohistochemistry and Western blotting.To further investigate molecular mechanisms,HT22 cells were treated in vitro with either SMS-LD medicated serum alone or in combination with AG490 and then exposed to CIH for 48 h.Our results indicate that SMS-LD significantly mitigated CIH-induced cognitive impairments in mice.Specifically,SMS-LD treatment enhanced dendritic spine density,ameliorated mitochondrial dysfunction,reduced oxidative stress,and activated the EPO/EPOR/JAK2 signaling pathway.Conversely,AG490 negated SMS-LD’s neuroprotective and cognitive improvement effects under CIH conditions.These findings suggest that SMS-LD’s beneficial impact on cognitive impairment and synaptic and mitochondrial integrity under CIH conditions may predominantly be attributed to the activation of the EPO/EPOR/JAK2 signaling pathway.

The effect of oxidative stress in myocardial cell injury in mice exposed to chronic intermittent hypoxia

Background Obstructive sleep apnea syndrome （OSAS） is an important risk factor for cardiovascular diseases. Chronic intermittent hypoxia （CIH） is considered to be one of the most important causes of cardiovascular diseases in OSA patients. This repeated hypoxia and reoxygenation cycle is similar to hypoxia-reperfusion injury, which initiates oxidative stress. In this study, we observed cardiocytes injury induced by CIH and the effect of N-acetylcysteine （NAC）. Methods Thirty ICR mice were randomly assigned to 3 groups： control, CIH and NAC （CIH＋NAC） groups. Malondialdehyde （MDA） and superoxide dismutase （SOD） of cardiocyte homogenates were measured. Serum lipids were measured by an instrument method. Serum cardiac troponin I （cTnl） was detected by enzyme-linked immunosorbent assays （ELISA）. Myocardium pathological sections were observed. Results （1） The SOD activity and MDA concentration of cardiocyte homogenates in the CIH group were significantly higher than in other groups （P 〈0.005）. The MDA concentration of the NAC group was lower than that of the control group （P 〈0.01）. （2） The serum cTnl concentration of the CIH and NAC groups was significantly higher than that of the control group （P 〈0.01）. （3） Serum triglyceride levels in the NAC group were lower than in the other groups （P 〈0.01）, while there were no significant differences in low density lipoprotein and high density lipoprotein among the three groups. （4） The degeneration of myocardium, transverse striation blurred, and fabric effusion were observed in tissue sections in the CIH and NAC groups. However, normal tissue was found in the control group. Conclusion The oxidative stress induced by CIH can injure cardiocytes and the injury effect can be partially inhibited by NAC.

Altered Wnt Signaling Pathway in Cognitive Impairment Caused by Chronic Intermittent Hypoxia： Focus on Glycogen Synthase Kinase-3β and β-catenin

Background： Cognitive impairment is a severe complication caused by obstructive sleep apnea （OSA）. The mechanisms of causation are still unclear. The Wntβ-catenin signaling pathway is involved in cognition, and abnormalities in it are implicated in neurological disorders. Here, we explored the Wntβ-catenin signaling pathway abnormalities caused by chronic intermittent hypoxia （CIH）, the most characteristic pathophysiological component of OSA. Methods： We divided 32 4-week-old male C57/BL mice into four groups of eight each： a CIH ＋ normal saline （NS） group, CIH ＋ LiCI group, sham CIH ＋ NS group, and a sham CIH ＋ LiCI group. The spatial learning performance of each group was assessed by using the Morris water maze （MWM）. Protein expressions of glycogen synthase kinase-β （GSK-β） and β-catenin in the hippocampus were examined using the Western blotting test. EdU labeling and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling staining methods were used, respectively, to determine the proliferation and apoptosis of neurons in the hippocampal dentate gyrus region. Results： Mice exposed to CIH showed impaired spatial learning performance in the MWM, including increased mean escape latencies to reach the target platform, decreased mean times passing through the target platform and mean duration in the target quadrant. The GSK-313 activity increased, and expression of β-catenin decreased significantly in the hippocampus of the CIH-exposed mice. Besides, CIH significantly increased hippocampal neuronal apoptosis, with an elevated apoptosis index. Meanwhile, LiCI decreased the activity of GSK-β and increased the expression of β-catenin and partially reversed the spatial memory deficits in MWM and the apoptosis caused by CIH. Conclusions： Wntβ-catenin signaling pathway abnormalities possibly play an important role in the development of cognitive deficits among mice exposed to CIH and that LiCI might attenuate CIH-induced cognitive impairment via Wntβ-catenin signaling pathway.

Chronic Intermittent Hypoxia and Hypertension:A Review of Systemic Inflammation and Chinese Medicine

Obstructive sleep apnea syndrome （OSAS） and hypertension commonly coexist. Clinical studies indicate that OSAS plays a key role in increasing the risk of prevalent hypertension. Chronic intermittent hypoxia （CIH） is the core pathological mechanism of OSAS, and has a close relationship with systemic inflammation. Growing evidence shows that CIH and hypertension are strongly related, involving markers or pathways indicative of systemic inflammation, such as high-sensitivity C-reactive protein （hs-CRP）, interteukin-6, nuclear factor-kappa B, tumor necrosis factor-α, interleukin-8 and p38 mitogen-activated protein kinase （MAPK）dependent pathways. Oxidative stress also plays an important role in this process, including in the activation of polymorphonuclear neutrophils. However, the pathophysiological and clinical significance of systemic inflammation in CIH and hypertension is not proven. This review article highlights the relationship between CIH and hypertension through systemic inflammation and the current interventions available in Chinese medicine, to offer a background for the future treatment of OSAS-related hypertension with integrative medicine.

Chronic intermittent hypoxia aggravates cardiomyocyte apoptosis in rat ovariectomized model

Background The prevalence of obstructive sleep apnea （OSA） increases after menopause in women, but remains under diagnosed because of social or lifestyle factors. It is important to evaluate the hazards of OSA on cardiovascular disease in menopausal women. We tested the hypothesis that chronic intermittent hypoxia （CIH） may aggravate cardiomyocyte apoptosis in ovariectomized （OVX） Sprague Dawley （SD） rats; the changes of anti-oxidation ability in cardiac muscles may be one of the reasons for cardiomyocyte apoptosis. Methods Forty-eight 60-day old female SD rats were randomly divided into a CIH group, OVX group, OVX±CIH （OC） group, and handled control （HC） group, and the rats were exposed either to CIH （nadir 02 6%） or handled normoxic controls. The changes of body weight and whole heart weight were measured. Super oxide dismutase （SOD） and malonaldehyde （MDA） were used to evaluate the level of oxidative stress. TdT-mediated dUTP nick end labeling （TUNEL） was used to measure apoptosis in each rat. Western blotting was used to measure apoptosis associated proteins in cardiac muscle samples from each rat. Results When compared with the HC and CIH groups, the levels of oxidative stress in the OC and OVX groups were significantly higher. The levels of SOD in the HC, CIH, OC, and OVX groups were （47.99±4.89）, （53.60±4.47）, （20.99±2.72）, and （30.64±3.79） mmol/mg protein; significantly increased in the CIH group （P 〈0.05） and significantly decreased in the OC （P 〈0.01） and OVX （P 〈0.05） groups. The levels of MDA in the HC, CIH, OVX, and OC groups were （1.63±0.20）, （1.93±0.77）, （3.30±0.39）, and （1.95_±0.20） mmol/mg protein; it significantly increased in the CIH （P 〈0.05）, OC （P 〈0.01）, and OVX （P 〈0.05） groups compared with the HC group. Bax protein expression was significantly increased and bcl-2 protein expression was significantly reduced after CIH compared with HC rats （P 〈0.05）. The protein expression of bax and bcl-2 in the OC group was not significantly different from the CIH group, but the ratio of bax/bcl-2 was significantly increased in the OC group （P 〈0.05）; this was associated with severe cardiomycyte apoptosis in the OC group. TUNEL confirmed this observation. Conclusions This study found that CIH may induce oxidative stress in OVX rats but not in CIH rats, and cause more severe cardiomyocyte apoptosis in OVX rats compared with CIH rats. This means that OVX rats exposed to CIH suffered more severe cardiac injury compared with CIH rats due to reduced antioxidation. These findings may partly explain the reason why OSA has a worse cardiovascular impact on menopausal women, and emphasize the importance of detection and early treatment of OSA in menopausal patients.

Sheng-Mai-San attenuates contractile dysfunction and structural damage induced by chronic intermittent hypoxia in mice

Sheng-Mai-San(SMS), a well-known Chinese medicinal plant formula, is widely used for the treatment of cardiac diseases characterized by deficiency of Qi and Yin syndrome. A mouse chronic intermittent hypoxia(CIH) model was established to mimic the primary clinical features of deficiency of Qi and Yin syndrome. Mice experienced CIH for 28 days(nadir 7% to peak 8% oxygen, 20 min per day), resulting in left ventricle(LV) dysfunction and structure abnormalities. After administration of SMS(0.55, 1.1, and 5.5 g·kg-1·d-1) for four weeks, improved cardiac function was observed, as indicated by the increase in the ejection fraction from the LV on echocardiography. SMS also preserved the structural integrity of the LV against eccentric hypotrophy, tissue vacuolization, and mitochondrial injury as measured by histology, electron microscopy, and ultrasound assessments. Mechanistically, the antioxidant effects of SMS were demonstrated; SMS was able to suppress mitochondrial apoptosis as indicated by the reduction of several pro-apoptotic factors(Bax, cytochrome c, and cleaved caspase-3) and up-regulation of the anti-apoptosis factor Bcl-2. In conclusion, these results demonstrate that SMS treatment can protect the structure and function of the LV and that the protective effects of this formula are associated with the regulation of the mitochondrial apoptosis pathway.

Effect of chronic intermittent hypoxia on the expression of Nip3, cell apoptosis, β-amyloid protein deposit in mice brain cortex

Background Chronic intermittent hypoxia （CIH） is the most important pathophysiologic feature of sleep apnea syndrome （SAS）. To explore the relationship between SAS and dementia, the effects of CIH on the expression of Nip3, neuron apoptosis and β-amyloid protein deposit in the brain cortex of the frontal lobe of mice were evaluated in this study.Methods Thirty male ICRmice＇were divided into four groups： control group （A, n=-10, sham hypoxia/reoxygenation）, 2 weeks CIH group （B, n=5）, 4 weeks CIH group （C, n=-5）, and 8 weeks CIH group （D, n=10）. The ICR mice were placed in a chamber and exposed to intermittent hypoxia （oxygen concentration changed periodically from （21.72±0.55）% to （6.84±0.47）% every two minutes, eight hours per day）. Neuron apoptosis of the cortex of the frontal lobe was detected by means of terminal deoxy-nucleotidyl transferase-mediated in situ end labeling （TUNEL）. Immunohistochemical staining was performed for measuring expression of Nip3 and β-amyloid protein. The ultrastructure of neurons was observed under a transmission electron microscope.Results TUNEL positive neurons in each square millimeter in the cortex of the frontal lobe were categorized by median or Riinto group A （1, 5.5）, group B （133, 13）, group C （252, 21）, and group D （318, 24）. There were significant differences among the above four groups （P=0.000）. The significance test was performed between the control group and each CIH group respectively： group A and B （P 〉0.05）; group A and C （P 〈0.01）; and group A and D （P 〈0.005）. The number of apoptotic neurons kept increasing in the ICR mice under CIH condition, and reached the peak in the group D, but there was no significant difference between groups B and C, between groups B and D, and between groups C and D. Nip3 positive neurons in each square millimeter in the cortex of the frontal lobe in each group were calculated by median or Ri as follows： group A （2, 5.5）, group B （117, 13）, group C （227, 26.2）, and group D（479, 21.4）. There were significant differences among the four groups （P=0.000）. The statistical test was performed between the control group and each CIH group respectively： groups A and B （P 〉0.05）; groups A and C （P〈0.005）; and groups A and D （P 〈0.005）. There was no significant difference between groups B and C, groups B and D, and groups C and D. The expression of Nip3 was closely correlated with neuron apoptosis in the brain （P 〈0.05）. The expression of β-amyloid protein in the brain of mice was negative in all CIH groups and the control group. Ultrastructure observation showed karyopyknosis of nucleus, swelling of chondriosomes, deposit of lipofuscins and degeneration of neural sheath in all CIH groups but not in the control group. Conclusion The results of this study indicate that CIH could up-regulate the expression of Nip3, and result in neuron apoptosis and ultrastructural changes in neurons of the frontal cortex.

Ginsenoside Rb1 alleviates chronic intermittent hypoxia-induced diabetic cardiomyopathy in db/db mice by regulating the adenosine monophosphate-activated protein kinase/Nrf2/heme oxygenase-1 signaling pathway

OBJECTIVE:To examine the protective effect of ginsenoside Rb1(Rb1),the main component of Renshen(Radix Ginseng),on cardiomyopathy in db/db mice exposed to chronic intermittent hypoxia(CIH)and explore the potential underlying mechanism of Rb1 in treating diabetic cardiomyopathy(DCM).METHODS:The db/db mice were randomly separated into five groups:normal control group,model group,Rb120 mg/kg group,Rb140 mg/kg group,and glucagon-like peptide-1(GLP-1)group.Mice were exposed to aircondition or CIH for 8 weeks,and Rb1 and GLP-1 were administrated before CIH exposure every day.Oral glucose tolerance test(OGTT),intraperitoneal insulin tolerance test(IPITT),total cholesterol(TC),triglyceride(TG),and high-density lipoprotein cholesterol(HDL-C)were detected to evaluate glycolipid metabolism.The level of insulin was detected by a mouse enzyme-linked immunosorbent assay(ELISA).Cardiac function was detected by echocardiography,and myocardial pathology was observed by hematoxylin-eosin and Masson staining.The expression of collagenⅠand collagenⅢwas detected by immunohistochemistry.Adenosine monophosphate-activated protein kinase(AMPK)/Nrf2/heme oxygenase-1(HO-1)signaling pathway was detected by Western blot and immunofluorescence.RESULTS:Rb1 treatment could improve glucose tolerance and the level of cardiac function indexes,and inhibit the level of oxidative stress indexes and the expression of collagenⅠand collagenⅢ.Moreover,Rb1 treatment enhanced AMPK phosphorylation and increased Nrf2 and HO-1 expression.CONCLUSION:Rb1 treatment alleviated CIH-induced diabetic cardiomyopathy and glycolipid metabolism disorders in db/db mice by inhibiting oxidative stress and regulating the AMPK/Nrf2/HO-1 signaling pathway.

ERK signaling mediates enhanced angiotensin II-induced rat aortic constriction following chronic intermittent hypoxia

Background Obstructive sleep apnea （OSA） has been recognized as an independent risk factor for systemic hypertension. The study investigated the functional consequences of chronic intermittent hypoxia （CIH） on aortic constriction induced by angiotensin II （Ang II） and the possible signaling involving ERK1/2 and contractile proteins such as myosin light chain kinase （MLCK）, myosin phosphatase targeting subunit （MYPT1） and myosin light chain （MLC）. Methods Male Wistar rats were randomly divided into CIH group and normoxia group and exposed to either CIH procedure or air-air cycles. Phosphorylation of ERK1/2, MYPT1 and MLC was assessed by Western blotting following constrictor studies in the presence or absence of PD98059 （10 μmol/L）. Results CIH-exposure resulted in more body weight gain and elevated blood pressure, which could be attenuated by pretreatment with PD98059. Endothelium-removed aortic rings from CIH rats exhibited higher constrictor sensitivity to Ang II （Emax： （138.56±5.78）% versus （98.45±5.31）% of KCI; pD2：7.98±0.14 versus 8.14±0.05, respectively）. CIH procedure exerted complex effects on ERK expressions （total ERK1/2 decreased whereas the ratio of phosphorylated to total ERK1/2 increased）. CIH aortas had higher MLCK mRNA and basal phosphorylation of MYPT1 and MLC. In parallel to greater increases in phosphorylation of ERK1/2, MYPT1 and MLC, Ang II-induced aortic constriction was significantly enhanced in CIH rats, which was largely reversed by PD98059. However vascular constriction of normoxia rats remained unchanged despite similar but smaller changing tendency of proteins phosphorylation. Conclusion These data suggest that CIH exposure results in aortic hyperresponsiveness to Ang II, presumably owing to more activated ERK1/2 signaling pathway.

Short-term Chronic Intermittent Hypobaric Hypoxia Alters Gut Microbiota Composition in Rats

Chronic intermittent hypobaric hypoxia (CIHH) is a treatment of moderate hypoxia that simulates high altitude interrupted by normoxia. Growing evidence shows that CIHH has multiple beneficial effects on

Impact of continuous positive airway pressure therapy for nonalcoholic fatty liver disease in patients with obstructive sleep apnea

BACKGROUND Obstructive sleep apnea(OSA)has been suggested as an independent risk factor for nonalcoholic fatty liver disease(NAFLD),and continuous positive airway pressure(CPAP)is the first-line therapy for OSA.AIM To clarify the efficacy of effective CPAP therapy on NAFLD of OSA patients by serum markers and transient elastography(TE)using FibroScan®(Echosens,Paris,France).METHODS We prospectively enrolled 123 consecutive patients with OSA who met the indications for CPAP.Liver fibrosis and steatosis were assessed using TE.Before and after 6 mo of CPAP therapy,serum markers and TE were assessed for all patients.The mean usage rate of CPAP therapy for 6 mo was arbitrarily calculated in each patient and expressed as“mean compliance index”(m-CI).RESULTS In 50 OSA patients with NAFLD,both aspartate aminotransferase(AST)and alanine aminotransferase(ALT)levels were significantly decreased after 6 mo of CPAP therapy.Univariate analysis showed that decreased body weight(BW),decreased body mass index(BMI),decreased AST level,decreased hemoglobin A1c,and high m-CI were significantly related with improved ALT level.In multivariate regression model adjusted for quantities of BW change during 6 mo of CPAP therapy,high m-CI tended to improve ALT level(P=0.051).All 17 OSA patients with NAFLD,high m-CI and no BMI changes showed significant improvements in AST and ALT levels.Meanwhile,no significant changes in TE data or serum fibrosis markers were seen.CONCLUSION Some NAFLD could be associated with chronic intermittent hypoxia due to OSA independent of BW changes.In those cases,adequate reoxygenation from effective CPAP therapy may improve NAFLD.

Intermittent hypoxia and isoniazid plus rifampicin affect hepatic ultrastructure in mice

Background Chronic intermittent hypoxia is the most important pathophysiologic feature of sleep apnea syndrome. The present study aimed to determine whether chronic intermittent hypoxia, which is associated with sleep apnea syndrome, can cause or increase damage to liver cell ultrastructure induced by isoniazid and rifampicin in mice. Methods Based on a 2x2 full factorial design consisting of two factors of chronic intermittent hypoxia and isoniazid plus rifampicin, 32 male C57B6J mice were randomized into the control group, the chronic intermittent hypoxia group, the isoniazid plus rifampicin group, and the chronic intermittent hypoxia ＋ isoniazid plus rifampicin group. Twelve weeks after treatment, we examined the ultrastructure of liver cells and quantitatively analyzed mitochondrial morphology in C57B6J mice. Results Chronic intermittent hypoxia did not significantly affect the ultrastructure of liver cells. The main effect of chronic intermittent hypoxia did not lead to an increase of mean profile area or mean perimeter of mitochondria, and a decrease of numerical density on area of mitochondria （all P 〉0.05）. Isoniazid plus rifampicin significantly affected liver cell ultrastructure. The main effect of isoniazid plus rifampicin resulted in an increase of mean profile area and mean perimeter of mitochondria, and a decrease of numerical density on area of mitochondria （all P 〈0.05）. Moreover, there was a positive interaction among the chronic intermittent hypoxia and the isoniazid plus rifampicin groups for mean profile area, mean perimeter, and numerical density on area of mitochondria （all P〈0.05）. Conclusion Chronic intermittent hypoxia and isoniazid plus rifampicin treatment lead to synergistic liver cell ultrastructural injury.

Protective effect of the extract of Yi-Qi-Fu-Mai preparation on hypoxia-induced heart injury in mice

Yi-Qi-Fu-Mai(YQFM) is extensively used clinically to treat cardiovascular diseases in China. To explore the anti-hypoxia effect of the extract of YQFM preparation(EYQFM), the EYQFM(1.4, 2.8, and 5.5 g·kg-1·d-1) was assessed for its heart-protective effect in a chronic intermittent hypoxia(CIH) animal model(oxygen pressure 7%-8%, 20 min per day) for 28 days of treatment. Betaloc(0.151 6 g·kg^(-1)·d^(-1)) was used as a positive control. The histopathological analyses of heart in CIH mice were conducted. Several cardiac state parameters, such as left ventricular ejection fractions(EF), stroke volume(SV), expression of creatine kinase(CK), lactate dehydrogenase(LDH), superoxide dismutase(SOD), and malondialdehyde(MDA) were measured. The results showed that treatment with EYQFM markedly reversed swelling of the endothelial cells and vacuolization in the heart when compared with the model group. Further study demonstrated that EYQFM significantly improved ventricular myocardial contractility by increasing EF and SV. In addition, EYQFM inhibited the activity of CK, LDH, decreased the level of MDA and improved SOD activity. The results demonstrated that EYQFM significantly improved the tolerability of myocardium to hypoxia and ameliorated the cardiac damage in the CIH model.